Continuous in vivo infusion of interferon-gamma (IFN-γ) preferentially reduces myeloid progenitor numbers and enhances engraftment of syngeneic wild-type cells in Fancc-/- mice

Fanconi anemia (FA) is characterized by bone marrow (BM) failure and cancer susceptibility. Identification of the cDNAs of many FA complementation types allows the potential of using gene transfer technology to introduce functional cDNAs as transgenes into autologous stem cells and provide a cure fo...

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Bibliographic Details
Published in:Blood 2004-08, Vol.104 (4), p.1204-1209
Main Authors: Li, Xiaxin, Yang, Yanzhu, Yuan, Jin, Hong, Ping, Freie, Brian, Orazi, Attilio, Haneline, Laura S., Clapp, D. Wade
Format: Article
Language:English
Subjects:
Animals
Apoptosis - drug effects
Biological and medical sciences
Bone Marrow Transplantation - methods
Cell Count
Cell Cycle Proteins
Chromosome fragility (bloom syndrome, ataxia telangiectasia, fanconi anemia, x-linked mental retardation...)
DNA-Binding Proteins - deficiency
Fanconi Anemia - drug therapy
Fanconi Anemia - therapy
Fanconi Anemia Complementation Group C Protein
Fanconi Anemia Complementation Group Proteins
Graft Survival - drug effects
Hematologic and hematopoietic diseases
Infusions, Parenteral
Interferon-gamma - administration & dosage
Interferon-gamma - therapeutic use
Medical genetics
Medical sciences
Mice
Mice, Knockout
Myeloid Cells - drug effects
Myeloid Progenitor Cells - drug effects
Nuclear Proteins - deficiency
Transplantation Conditioning - methods
Transplantation, Isogeneic
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Summary:Fanconi anemia (FA) is characterized by bone marrow (BM) failure and cancer susceptibility. Identification of the cDNAs of many FA complementation types allows the potential of using gene transfer technology to introduce functional cDNAs as transgenes into autologous stem cells and provide a cure for the BM failure in FA patients. Previous studies in FA murine models and in a phase 1 clinical trial suggest that myelopreparation is required for significant engraftment of exogenous, genetically corrected stem cells. Since myeloid progenitors from Fancc-/- mice and human Fanconi anemia group C protein (FANCC) patients have increased apoptosis in response to interferon γ (IFN-γ) in vitro, we hypothesized that IFN-γ may be useful as a nongenotoxic, myelopreparative conditioning agent. To test this hypothesis, IFN-γ was administered as a continuous infusion to Fancc-/- and wild-type (WT) mice for 1 week. Primitive and mature myeloid lineages were preferentially reduced in IFN-γ-treated Fancc-/- mice. Further, IFN-γ conditioning of Fancc-/- recipients was sufficient as a myelopreparative regimen to allow consistent engraftment of isogenic WT repopulating stem cells. Collectively, these data demonstrate that Fancc-/- hematopoietic cell populations have increased hypersensitivity to IFN-γ in vivo and that IFN-γ conditioning may be useful as a nongenotoxic strategy for myelopreparation in this disorder. (Blood. 2004;104:1204-1209)
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2004-03-1094